Isothiazolinone solutions

ABSTRACT

Compounds of the general formula ##STR1## are cyclized to the corresponding isothiazolinone using a carbonyl halide of the formula RCOX where R is halogen or alkyl and X is halogen. R 3  and R 4  are preferably such as to form a 5 or 6 membered ring. Useful carbonyl halides are phosgene and propionyl chloride. Using acyl halides such as propionyl chloride, a mixture of the isothiazolinone and a salt of the carboxylic acid can be obtained, for example an essentially equimolar mixture of 2-methyl-4,5-trimethyl-4-isothiazolin-3-one and sodium propionate.

This is a division of application Ser. No. 07/971,809, filed Nov. 5,1992, now U.S. Pat. No. 5,336,777, which is a continuation of Ser. No.07/582,261, filed Sep. 13, 1990, now abandoned.

The present invention relates to a process for the preparation ofisothiazolinones, particularly tri- ortetra-methylene-4-isothiazolin-3-ones.

Isothiazolinones are a class of compounds which are known to have usefulantimicrobial activity and several compounds of this type arecommercially available and are used as industrial biocides, particularlyas bactericides.

A new class of isothiazolinones, specifically those of the type4,5-polymethylene-4-isothiazolin-3-one, are disclosed in GB 2087388. Incompounds of this type, the polymethylene chain contains 3 or 4 carbonatoms or is a chain substituted by a lower alkyl radical having from 1to 4 carbon atoms. These compounds can be prepared by a process whereina carbamoylcyclanone is converted to the correspondingcarbamoylthiocyclanone which is then cyclised to form the desiredisothiazolin-3-one product. The first stage of this procedure useshydrogen sulphide and gaseous hydrogen chloride and the second stage iscarried out in an alcohol solution in the presence of sodiummetaperiodate previously fixed to acidic alumina.

According to GB 2176187, the procedure GB 2087388 has the disadvantageof being difficult to transfer to the industrial level. As analternative to the procedure of GB 2087388, GB 2176187 discloses anintermediate product which is a 2-alkylthio- or2-aralkylthio-1-cycloalkene-1-carboxamide, which can be converted to thecorresponding sulphoxide by the action of m-chloroperbenzoic acid, orthe action of hydrogen peroxide in an acidic medium, and the resultingsulphoxide can be cyclised to the desired final product, which is4,5-tri or tetra-methylene-4-isothiazolin-3-one. The sulphoxide iscyclised in a suitable solvent such as methylene chloride in thepresence of an acid chloride. The acid chloride specifically disclosedis thionyl chloride, which is used in all of the working examples.

The isothiazolinone is typically precipitated during the cyclisationstep and can be separated from the reaction medium and washed to removeany excess thionyl chloride and reaction products such as sulphurdioxide. However, since many isothiazolinones are skin irritants orsensitisers, on a commercial scale separation of solid isothiazolinonehas to be effected in a closed vessel and this adds to the productioncosts. Accordingly we prefer to contact the precipitatedisothiazolinone, together with the reaction medium, with water in whichthe isothiazolinone is soluble giving an aqueous solution of theisothiazolinone which is readily separated from the reaction medium andwhich gives fever containment problems. However, using such a procedure,the excess unreacted thionyl chloride can cause the formation ofundesirable tars as by-products. Furthermore, thionyl chloride isdifficult to separate from the isothiazolinone since the separation istypically effected by distillation and must be effected at a relativelylow temperature, preferably not greater than 50° C., in order to avoiddecomposition of the isothiazolinone product. Additionally, sulphurdioxide is a by-product of the cyclisation stage using thionyl chlorideand is extracted into the aqueous solution where it can cause breakdownof the isothiazolinone. Hence, whilst extraction into water from thereaction medium avoids the need for containment of solidisothiazolinone, it is not satisfactory for commercial use due toproblems arising from the presence of unreacted thionyl chloride and ofsulphur dioxide by-product.

We have found that the cyclisation step can be effected using otherreagents but many of those also give problems due to the formation ofundesirable tars, low yield of product or in other ways. However, wehave found that certain compounds can be used to effect the cyclisationto give good yields of the isothiazolinone product with little if anytar by-products and with no reaction products which cause undesirablebreakdown of the reaction product.

According to the present invention there is provided a process for thepreparation of an isothiazolin-3-one derivative which comprisescyclising a compound of the general formula I ##STR2## in the presenceof an organic solvent and a carbonyl halide of the general formula RCOX,wherein

R is a halogen atom or an alkyl group;

R¹ is an alkyl group or an aralkyl group;

R² is a hydrogen atom or an optionally substituted hydrocarbyl group;

R³ and R⁴ may be the same or different, and are hydrogen, halogen, or anoptionally substituted hydrocarbyl group or R³ and R⁴ together with thecarbon atoms to which they are attached, form an optionally substitutedring; and

X is a halogen atom.

The compound of formula I is a sulphinyl carboxamide and may be acompound as described in GB 2176187. The compound of formula I istypically one in which R¹ is a group which contains 1 to 12 carbon atomsand very conveniently is one in which R¹ is an aralkyl group for examplean aralkyl group containing up to 10 carbon atoms and especially abenzyl group. The group R² may be a hydrogen atom when the productobtained will be an isothiazolinone substituted only by the groups R³and R⁴. Alternatively, R² can be a hydrocarbyl group such as an alkyl,aryl, cycloalkyl, alkaryl, aralkyl or alkenyl group containing up to 20carbon atoms, especially i to 12 carbon atoms. Any substituents presentin the group R² should be such as not to deleteriously affect theproperties of the final isothiazolinone product. The substituents may benitro groups, halogen atoms, oxyhydrocarbon groups or halohydrocarbongroups. Typically the group R² is unsubstituted and preferably is analkyl group. Very preferably R² is a lower alkyl group, that is an alkylgroup containing not more than six carbon atoms, for example a methylgroup.

Preferably at least one of the groups R³ and R⁴ is other than hydrogen.If R³ and/or R⁴ is halogen, it is typically chlorine. If R³ and/or R⁴ isa hydrocarbyl group, it is typically an alkyl group which contains 1 to12 carbon atoms. Alternatively, R³ and R⁴ may form a ring, for example abenzene ring. However, we have found that the process of the presentinvention is especially useful when R³ and R⁴ together form apolymethylene group of the type --(CH₂)_(n) -- where n is an integerwhich has a value of at least three. If R³ and/or R⁴ are substituted ortogether form a substituted ring, the substituents should be such as notto deleteriously affect the properties of the final isothiazolinoneproduct. Suitable substituents may be nitro groups, halogen atoms,oxyhydrocarbon groups and halohydrocarbon groups. Typically R³ and/or R⁴are unsubstituted alkyl groups or together form an unsubstituted ring,especially a cycloalkene ring.

According to a preferred aspect of the present invention, a compound ofthe general formula II is cyclised ##STR3## where R¹ and R² are aspreviously defined; and m has a value of 3 or 4.

The value of m is typically three since such compounds produceisothiazolinone derivatives which have particularly useful properties asindustrial biocides.

The carbonyl halide is conveniently one in which X is chlorine. Thegroup R can be an alkyl group, for example one containing up to 12carbon atoms, and is preferably a lower alkyl group, as previouslydefined herein. Alternatively R can be a halogen atom and the preferredhalogen atom is chlorine. We have obtained useful results using, as thecarbonyl halide, phosgene (R and X are both chlorine) and propionylchloride (R is an ethyl group and X is chlorine).

Any suitable organic solvent may be used and it is preferred to usesolvents which are immiscible with water such as hydrocarbons,halohydrocarbons and higher ethers and ketones. It is generallypreferred to use a hydrocarbon solvent, for example a hydrocarbonsolvent having a boiling point of at least 50° C. and typically onehaving a boiling point not exceeding 150° C. The solvent may be acommercially available hydrocarbon mixture and may be an aliphatic oraromatic hydrocarbon, or a mixture thereof. It is generally preferredhowever that the solvent is an aliphatic hydrocarbon such as a petroleumether having a boiling point in the range 100° to 120° C.

As indicated previously herein, the isothiazolinone reaction product issusceptible to degradation at elevated temperatures. Furthermore, wehave found that the yield of the isothiazolinone product is reduced athigher reaction temperatures. Hence, it is preferred that thecyclisation process of the present invention is effected at atemperature of not more than 50° C. and preferably not more than 30° C.If the carbonyl halide is an acyl halide such as propionyl chloride, itis generally preferred that the reaction temperature does not exceed 20°C. and especially is not more than 10° C. We have found that there is anexotherm during the cyclisation step and this can result in atemperature rise of about 10° C. Accordingly, the reaction mixture isvery desirably agitated throughout the reaction and is cooled in orderto prevent an excessive temperature rise. We have obtained satisfactoryyields of product when using an acyl halide and affecting the reactionat an initial temperature of 0°-5° C. In order to control thetemperature, and to minimise the effects of the reaction exotherm, it isconvenient to add the carbonyl halide to the sulphinyl carboxamide offormula I, or especially formula II, over an extended period of time,for example 15 minutes to three hours, conveniently one hour using anacyl halide. If the carbonyl halide is phosgene, this may be used in thegaseous state by bubbling through the liquid reaction medium or may becooled and condensed and added dropwise to the reaction medium over anextended period of time which is conveniently two hours.

The cyclisation reaction occurs readily and typically is completebetween 0.5 and 3 hours, for example one to two hours, after theaddition of the carbonyl halide has finished. The progress of thereaction can be monitored by suitable analytical means, for example byhigh performance liquid chromatography.

The sulphinyl carboxamide and carbonyl halide are preferably reactedtogether in essentially equimolar amounts or using a slight molar excessof the carbonyl halide. Thus, the molar proportions of sulphinylcarboxamide to carbonyl halide are typically in the range 2:1 to 1:2,and especially are in the range 1:1 to 1:1.5, particularly 1:1.05 to1:1.2.

When the cyclisation reaction is complete, the product mixture isconveniently mixed with water, preferably at least an equal volume ofwater. The isothiazolinone product is extracted into the water to forman aqueous solution and the amount of water used should be sufficient todissolve all of the isothiazolinone product. Reaction by-productsextracted into the aqueous phase maybe removed by washing the aqueoussolution with a suitable organic solvent which is conveniently the samematerial as is used as the solvent for the cyclisation reaction.

The aqueous phase typically contains a weakly associated salt of theisothiazolinone together with an acid derived from the carbonyl halide,for example hydrochloric acid or propionic acid. The aqueous phase ispreferably neutralised in order to avoid degradation of the product onstorage, particularly in the presence of strong mineral acid.

The neutralisation may be effected using any suitable base. Since theisothiazolinone product is sensitive to strongly alkaline conditions, itis preferred to agitate the mixture vigorously during the addition ofthe base. The base is conveniently an aqueous solution of an alkalinemetal hydroxide, for example sodium hydroxide. Neutralisation iseffected to give a pH which is in the range 4 to 9 and especially is notmore than 7.5, for example in the range 6.5 to 7.5. During theneutralisation it is preferred that the temperature should not beallowed to rise excessively and it is especially preferred that thetemperature does not exceed 25° C.

The aqueous solution contains the isothiazolinone and a salt of an acidderived from the carbonyl halide. The relative molar proportions of theisothiazolinone and the salt are similar to the proportions of sulphinylcarboxamide and carbonyl halide used to effect the cyclisation reaction.Hence, the aqueous solution typically contains the isothiazolinone andthe salt in essentially equimolar proportions, and in general with aslight molar excess of the salt.

The salt may be a salt of a carboxylic acid, for example sodiumpropionate.

A particular useful aqueous solution contains a4,5-polymethylene-4-isothiazolin-3-one together with a salt of thegeneral formula

    MOCOR.sup.5

where

M is an alkali metal; and

R⁵ is an alkyl group.

M is conveniently sodium. The group R⁵ is derived from the carbonylhalide and corresponds to the group R when this is an alkyl group. Aparticular salt is sodium propionate (M is sodium and R⁵ is ethyl).

The process of the present invention may be used to obtain4,5-polymethylene-4-isothiazolin-3-ones as described in GB 2087388.Using the process of the present invention we have obtained2-methyl-4,5-trimethylene-4-isothiazolin-3-one in good yields. Inparticular, we have obtained an aqueous solution containing2-methyl-4,5-trimethylene-4-isothiazolin-3-one and sodium propionate.Such a solution typically contains essentially equimolar proportions ofthe isothiazolinone and the salt, and especially contains a slight molarexcess, of up to 1.5 moles, of the salt.

The aqueous solution may be diluted to give a desired concentration ofthe isothiazolinone, for example from 1 to 102 by weight ofisothiazolinone. The solution may be used as an industrial biocide,particularly as a bactericide, as is disclosed on GB 2087388.

The present invention is described in more detail hereafter in thefollowing illustrative, non-limiting examples.

EXAMPLE 1

Into a 150 cm³, 4-necked glass reaction flask fitted with an anchoragitator, thermometer, dropping funnel and condenser were charged 75 gof petroleum ether (100-120). 34.72 g ofN-methyl-2-benzylsulphinyl-1-cyclopentene-1-carboxamide of 94.7% purity(obtainable as described in GB 2176187) were then charged to thepetroleum ether in the reaction flask with agitation and the suspensionwas cooled to 0°-5° C.

12.72 g of propionyl chloride were charged to the suspension over aperiod of one hour, maintaining the temperature at 0°-5° C. throughout.The suspension was agitated for a further one hour when high performanceliquid chromatography analysis showed the reaction to be complete.

230 cm³ of water were charged to a 500 cm³ flask having an agitator anda bottom run-off and the flask and its contents were cooled to 10°-15°C. with agitation. The suspension obtained as described previously wasthen added to the water whilst continuing to agitate the contents of theflask. Agitation was stopped, the two layers were allowed to separateand the lower aqueous layer containing the isothiazolinone product wasrun off. This layer was washed twice with petroleum ether (100-120),using 4.5 g for each wash, to remove traces of benzyl chloride. Thepetroleum ether solutions were combined for solvent recovery anddisposal of benzyl chloride.

The separated aqueous layer was adjusted to pH 7 with 47% by weightcaustic soda liquor with efficient agitation, maintaining thetemperature at below 25° C. throughout. One gramme of a diatomaceousearth filter aid and one g of activated carbon were then charged, themixture was filtered and a small follow through water wash applied.

By analysis, the final aqueous solution was found to contain2-methyl-4,5-trimethylene-4-isothiazolin-3-one and sodium propionate,the latter component being in a slight molar excess. 17.46 g of the2-methyl-4,5-trimethylene-4-isothiazolin-3-one were obtained,representing a yield of 90% of theory based on theN-methyl-2-benzylsulphinyl-1-cyclopentene-1-carboxamide startingmaterial.

EXAMPLE 2

Into a 500 cm³, 4-necked, glass reaction flask fitted with an anchoragitator, thermometer, dropping funnel and condenser were charged 150 gof petroleum ether (100-120). The contents of the flask were agitatedand 86.51 g of N-methyl-2-benzylsulphinyl-1-cyclopentene-1-carboxamideof 91.2% purity (obtainable as described in GB 2176187) were added andthe temperature was adjusted to 25° to 30° C.

36.12 g of phosgene was condensed to the liquid phase using a condensercooled with a solid carbon dioxide/ethanol mixture. This liquid phosgenewas charged to the reaction flank dropwise over a period of two hourswhilst continuing to agitate and maintaining the temperature at 25° to30° C. by external cooling.

Completion of the reaction was tested using high performance liquidchromatography analysis. Reaction was found to be complete afteragitation for a further two hours at 25° to 30° C. after all of thephosgene had been added.

Residual phosgene in the product mixture was removed by the passage of astream of nitrogen through the product mixture over a period of onehour. 120 cm³ of water were then added to the mixture at 25° C.

355 cm³ of water were charged to a one dm³ flask having an agitator anda bottom run off. The flask and its contents were maintained at 20° to25° C., and the contents were agitated during the addition of thereaction mixture plus water obtained as previously described. Agitationwas terminated and the liquid phases were allowed to separate. The loweraqueous layer which contained the isothiazolinone product was run off.This layer was then extracted with 50 g of petroleum ether (100-120) toremove residual by-product benzyl chloride.

The separated aqueous later was adjusted to pH 4 to 6 by the slowaddition of 47% by weight caustic soda liquor whilst agitatingefficiently and maintaining the temperature at below 25° C.

2 g of activated carbon and 2 g of a diatomaceous earth filter aid wereadded to the agitated aqueous solution, which was then filtered. Thefiltered solution was diluted to give a 6% by weight concentration of2-methyl-4,5-trimethylene-4-isothiazolin-3-one. By analysis it wasdetermined that the yield of the isothiazolinone was 93.7% of theorybased on the N-methyl-2-benzylsulphinyl-1-cyclopentene-1-carboxamidestarting material.

We claim:
 1. An aqueous solution comprising an isothiazolinone offormula I: ##STR4## wherein R² is hydrogen or optionally substitutedhydrocarbyl;m is 3 or 4; and a salt of formula 2

    MOCOR.sup.5                                                2

whereinM is an alkali metal; and R⁵ is C₁₋₁₂ -alkyl.
 2. A solution asclaimed in claim 1 wherein m is
 3. 3. A solution as claimed in claim 1wherein R² is C₁₋₁₂ -alkyl.
 4. A solution as claimed in claim 1 whereinR² is C₁₋₆ -alkyl.
 5. A solution as claimed in claim 1 wherein theisothiazolinone is 2-methyl-4,5-trimethyleneisothiazolin-3-one.
 6. Asolution as claimed in claim 1 wherein M is sodium.
 7. A solution asclaimed in claim 1 wherein R⁵ is C₁₋₆ -alkyl.
 8. A solution as claimedin claim 1 wherein R⁵ is ethyl.
 9. A solution as claimed in claim 1which contains a molar excess of the salt in an amount of up to 1.5moles of the salt for each mole of the isothiazolinone.
 10. A solutionas claimed in claim 1 having a pH in the range 4 to
 9. 11. A solution asclaimed in claim 1 which contains from 1 to 10% by weight of theisothiazolinone.